Multidimensional genomic signature of human liver growth and hypertrophy

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Background: Normal human liver has remarkable plasticity and regenerative capacity: Resections of up to 60% of the liver are routinely performed in the context of oncological surgery or living donor liver transplantation. However, key questions regarding the roles and the cooperation of hepatic cell types such as hepatocytes, vascular, immune, stellate and hepatocyte stem cell compartments and their underlying genomic programs in this process – particularly in human liver – remain unanswered. There is pressing medical need for novel therapeutic approaches to enhance liver regeneration in the context of liver surgery and in cirrhotic organ damage.Aims: Using a unique clinical infrastructure, we aim to understand the cellular programs and origins of regenerative processes in human liver using deep single cell and epigenetic analyses.Own proceeding work: The applicants build on their expertise in liver epigenetics and functional genomics and have established a unique analysis pipeline.Work plan: The applicants will use the clinical setting of therapeutically induced liver regeneration through portal vein embolization and in-situ split surgery before oncological liver resection. Hypertrophied and control liver from the same individual – thereby providing an inherent control for interindividual variation – will undergo single cell RNA and NOMe sequencing of freshly isolated hepatocytes and non-parenchymal cells. This data will be complemented by nuclear RNA sequencing from fresh frozen liver samples and by spatial information generated from laser capture cryo-microdissection of zonated parenchymal and major non-parenchymal cell compartments. Characteristic genomic signatures will further be verified by immunohistochemistry and RNA in situ hybridization. Bioinformatic integration will ultimately provide a spatially resolved and dynamic map of the cellular and tissue genomic programs of liver growth and hypertrophy. Conclusion: This project provides a unique opportunity to study the regeneration of a human organ (i.e. liver) on a single cell and tissue level in a clinically relevant, well controlled and ethically sound setting. The results will provide profound new insights into human liver biology and point out mechanisms to therapeutically tackle liver regeneration and remodeling.